Bottom Line:
CD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self.Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs in both autoimmune and infectious disease has continued to expand.In addition, advances made in the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, techniques and antibodies are discussed.

ABSTRACTCD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self. Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs in both autoimmune and infectious disease has continued to expand. This review examines the recent advances on the role CD4+ CD25+ Tregs may be playing in various diseases regarding progression or protection. In addition, advances made in the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, techniques and antibodies are discussed. Ultimately, an overall understanding of the exact mechanism which CD4+ CD25+ Tregs implement during disease progression will enhance our ability to manipulate CD4+ CD25+ Tregs in a clinically beneficial manner.

fig01: Induced and natural CD4+ CD25+ Tregs have been found to express many different surface markers and cytokines. It is believed that one of the factors involved in Treg induction are antigen-presenting DC (1). Once induced, CD4+ CD25+ Tregs are capable of acting on effector T cells through either cell–cell contact (2) or cytokine secretion (3). TGF-β has been involved in Treg function through both of these pathways.

Mentions:
As for the third question, research has shown that both natural and adaptive CD4+ CD25+ Tregs are able to suppress the immune system by using both non-specific [27, 28] and antigen-specific responses [29–32]. Many in vivoand in vitrostudies have inves-tigated the suppressive functionality of CD4+ CD25+ Tregs; however, no general mechanism has emerged to date on how Tregs act on cells. It has been shown that the suppressive function needs direct cell–cell contact and/or release of cytokines (Fig. 1) [27, 29]. Sometimes Tregs seem to act indirectly by involving other cell sub-types, in particular dendritic cells (DCs) [33]. Generally, Tregs need to be activated to exert their suppressive function [34]. When activated, CD4+ CD25+ Tregs can secrete various cytokines into the milieu, such as IL-10 and TGF-β[27, 29]. However, TGF-β which is only found cell-bound in non-activated CD4+ CD25+ Tregs, seems to be of equal importance for contact-dependent suppression as the secreted form (Fig. 1) [27]. There are conflict-ing data on the impact of soluble cytokines on suppression in vitro, however, the in vivo role of cytokines has been confirmed [35, 36]. Most proba-bly, there is not just one route that the CD4+ CD25+ Tregs use to exert their functions on their target cells; this complex system could be the result of the CD4+ CD25+ Tregs maximizing their efficiency or some kind of specificity of suppressing the immune response by having multiple mechanisms at their disposal. This concept would allow the CD4+ CD25+ Tregs to have the ability to express their function on a variety of target cells in different environments as the situation dictates. However, the research to date has not yet led us to a conclusive outcome on how exactly the CD4+ CD25+ Tregs exert their suppres-sive abilities.

fig01: Induced and natural CD4+ CD25+ Tregs have been found to express many different surface markers and cytokines. It is believed that one of the factors involved in Treg induction are antigen-presenting DC (1). Once induced, CD4+ CD25+ Tregs are capable of acting on effector T cells through either cell–cell contact (2) or cytokine secretion (3). TGF-β has been involved in Treg function through both of these pathways.

Mentions:
As for the third question, research has shown that both natural and adaptive CD4+ CD25+ Tregs are able to suppress the immune system by using both non-specific [27, 28] and antigen-specific responses [29–32]. Many in vivoand in vitrostudies have inves-tigated the suppressive functionality of CD4+ CD25+ Tregs; however, no general mechanism has emerged to date on how Tregs act on cells. It has been shown that the suppressive function needs direct cell–cell contact and/or release of cytokines (Fig. 1) [27, 29]. Sometimes Tregs seem to act indirectly by involving other cell sub-types, in particular dendritic cells (DCs) [33]. Generally, Tregs need to be activated to exert their suppressive function [34]. When activated, CD4+ CD25+ Tregs can secrete various cytokines into the milieu, such as IL-10 and TGF-β[27, 29]. However, TGF-β which is only found cell-bound in non-activated CD4+ CD25+ Tregs, seems to be of equal importance for contact-dependent suppression as the secreted form (Fig. 1) [27]. There are conflict-ing data on the impact of soluble cytokines on suppression in vitro, however, the in vivo role of cytokines has been confirmed [35, 36]. Most proba-bly, there is not just one route that the CD4+ CD25+ Tregs use to exert their functions on their target cells; this complex system could be the result of the CD4+ CD25+ Tregs maximizing their efficiency or some kind of specificity of suppressing the immune response by having multiple mechanisms at their disposal. This concept would allow the CD4+ CD25+ Tregs to have the ability to express their function on a variety of target cells in different environments as the situation dictates. However, the research to date has not yet led us to a conclusive outcome on how exactly the CD4+ CD25+ Tregs exert their suppres-sive abilities.

Bottom Line:
CD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self.Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs in both autoimmune and infectious disease has continued to expand.In addition, advances made in the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, techniques and antibodies are discussed.

ABSTRACTCD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self. Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs in both autoimmune and infectious disease has continued to expand. This review examines the recent advances on the role CD4+ CD25+ Tregs may be playing in various diseases regarding progression or protection. In addition, advances made in the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, techniques and antibodies are discussed. Ultimately, an overall understanding of the exact mechanism which CD4+ CD25+ Tregs implement during disease progression will enhance our ability to manipulate CD4+ CD25+ Tregs in a clinically beneficial manner.